Project Summary/Abstract Timed eating is recognized for its significant contribution to body weight regulation. Disruption of sleep-wake cycles from a predominantly diurnal (daytime) lifestyle to a delayed lifestyle leads to disrupted circadian rhythms and metabolic dysfunction. In our R21 (DK100787), we studied healthy, normal weight adults in a randomized, cross-over design comparing the effects of eating an isocaloric diet for 8 wks on a daytime vs a delayed schedule, with a constant sleep-wake cycle. Our preliminary results indicate weight, respiratory quotient, trunk fat, insulin, total cholesterol, and adiponectin decreased on the daytime schedule, while triglycerides and glucose increased on the delayed schedule. Also, in the daytime condition, the circadian phase of ghrelin was advanced and that of leptin was delayed, but melatonin phase remained unchanged vs. the delayed condition. Our results provide the first experimental evidence that daytime eating compared with delayed eating promotes weight loss and a positive profile for fuel oxidation and hormonal markers, and positively alters circadian rhythm phase in normal weight adults. Notably, the metabolic effects and their underlying circadian mechanisms of such eating patterns have not been investigated rigorously in experimental studies among obese populations. We hypothesize that a daytime compared with a delayed eating schedule, with constant sleep-wake and activity levels, will decrease weight, improve metabolic profiles and positively impact circadian-mediated responses in obese persons, decreasing the risk for developing metabolic syndrome and diabetes. Forty healthy men and women, ages 21- 50, with a BMI of 30-50 kg/m2 will participate in a free-living randomized cross-over experiment comparing a daytime eating schedule (0800h-1900h) to a delayed eating schedule (1200h-2300h), with comparable energy and macronutrient content, and constant sleep-wake periods (2300h-0700h) and exercise (<30 min/d, <3 d/wk). Our metabolic kitchen will provide all food for 8 wks during each condition, separated by a 2-wk washout. Protocol adherence will be monitored closely with food logs, weighing of food, pictures for portion size assessment of any outside food eaten, actigraphy, and daily self-reports of sleep-wake and exercise. Assessments will occur 4 times, pre- and post- each 8-wk eating condition, during which we will measure: weight, body composition, respiratory quotient and resting energy expenditure; fasting levels of insulin, glucose, cholesterol, triglycerides, adiponectin, non-esterified fatty acids and C reactive protein; and levels of leptin, ghrelin, melatonin, glucose and cortisol, and gene expression from peripheral blood every 4h (7 times over 24h) to show circadian rhythm phase changes between the eating conditions. We will also examine mechanisms underlying these changes through frequently sampled intravenous glucose tolerance testing to determine insulin sensitivity, pancreatic beta cell function, glucose effectiveness, and free fatty acid dynamics, and through subcutaneous white adipose tissue gene expression. This multi-faceted project will benefit from the investigators' expertise in eating behaviors/weight management, circadian and sleep biology, endocrinology and metabolism, and bioinformatics.